Huntington's Disease (HD) is a late onset progressive neurological disorder cause by the inheritance of a long CAG repeat coding for glutamine in the HD protein. Several lines of evidence indicate that lowering mutant HD gene expression may provide therapeutic benefit to the unfortunate victims of this disease. The broad long term goal of this work is to develop pharmaceutical agents designed to cause mild reductions in mutant Huntington's disease gene expression for prolonged periods. The project is based on our prior discovery that delivery of an inhibitor of an enzyme critical to long repeat gene expression directly to the mouse brain decreases the expression of a mutant mouse HD knock-in allele (HdhQ150) while increasing expression from the normal (short repeat, HdhQ7) version. There are several key questions about the overall strategy of targeting this process that will need to be addressed in order to translate our discovery into useful therapeutics. First, we will determine whether the positive results we obtained targeting the expression of long glutamine repeats in mouse brain also apply to the proline repeat just downstream of the glutamine repeat in the HD gene. Second, we will determine whether these inhibitors have effects on the expression of an allele that approximates the size found in most HD patients (HdhQ50). Third, we will determine the efficacy of this strategy in ameliorating the HD-like neurological abnormalities of a mouse model. These answers need to be addressed prior to the development of compounds with more favorable pharmacological characteristics. Thus, the proposed work represents the essential preliminary steps towards the development of therapeutics for HD patients.